Nikola Bregović

Dynamic Molecular Recognition in Solid State for Separating Mixtures of Isomeric Dicarboxylic Acids

Molecular recognition emerges from non-covalent interactions and is of paramount importance for understanding of biological processes, ranging from enzymatic activity to DNA base pairing, as well as in the design of functional supramolecular systems, for example, molecular motors, sensors, ion receptors, or systems used in waste management. In the specific area of selective anion binding, numerous anion receptors (hosts) and sensors have been developed. The study of anion binding has traditionally been performed in solution where the host often experiences conformational freedom to form complexes with a wide range of guests. However, selectivity in separation has usually been achieved only upon crystallization, emphasizing the importance of intermolecular interactions in rigid crystal environment which lock the conformation of the host giving rise to its selectivity. In this context, recent advances in chemical reactivity achieved using mechanochemistry indicate that the concepts of supramolecular chemistry, such as templating, may be applicable also to solvent-free reactions. Mechanochemical reactivity can be highly dynamic and has thus far been employed for solid-state differentiation between enantiomers, supramolecular metathesis reactions, and for thermodynamic product selection. Although these reactions show specific interaction patterns between molecules comprising their respective solid phases, the possibility of selective binding and separation of target guest molecules from solid mixtures is, besides the pioneering studies by Etter and Caira, still an unexplored area. Here we focus on recognition and separation of isomeric or geometrically similar dicarboxylic acids (Scheme 1) from either their solid or solution mixtures using principles of supramolecular chemistry. The chosen acids belong to a class of guests of high biological and industrial relevance, and a considerable effort has been put into developing their sensors and receptors. Typically, the receptor for each dicarboxylate had to be meticulously designed because of the specific geometry of each acid molecule and their differing physicochemical properties. The importance of separation of the maleic/fumaric acid (H2mal/H2fum) stereoisomeric pair is not only related to the specific diastereomer recognition, but also arises from their conflicting biochemical behavior and abundant use of H2fum in food and pharmaceutical industry. We show here that the flexible polyamine receptor L (Scheme 1) discriminates among H2mal/H2fum diastereomers, succinic acid (H2suc), and three isomers of benzenedicarboxylic acid, by adapting its conformation and finally forming different solid hydrogenbonded (HB) frameworks. Regardless of whether the recognition takes place in the solid state by milling or by crystallization from solution, the resulting supramolecular complexes are the same and the selectivity bias of L towards the guest acids is fully retained. Milling improved yields to quantitative and almost eliminated the use of solvent. L proved to be an exceptional receptor for H2mal, also on the gram scale, excluding it from solid mixtures with even five other acids or from mixtures where there is a large surplus of a competing acid. Reacting L and H2mal in methanol (MeOH) or ethanol (EtOH) solutions yielded isoskeletal solvated solids, 1a (Table 1 and Section S.2 in the Supporting Information), Scheme 1. Dicarboxylic acids and the polyamine host L. The host binds anions as a cation (HL) resulting from protonation of the central amino group.

Desmotropy, Polymorphism, and Solid-State Proton Transfer: Four Solid Forms of an Aromatic o-Hydroxy Schiff Base

The Schiff base derived from salicylaldehyde and 2-amino-3-hydroxypyridine affords a diversity of solid forms, two polymorphic pairs of the enol-imino (D1 a and D1 b) and keto-amino (D2 a and D2 b) desmotropes. The isolated phases, identified by IR spectroscopy, X-ray crystallography, and (13)C cross-polarization/magnetic angle spinning (CP/MAS) NMR spectroscopy, display essentially planar molecular conformations characterized by strong intramolecular hydrogen bonds of the O-H⋅⋅⋅N (D1) or N-H⋅⋅⋅O (D2) type. A change in the position of the proton within this O⋅⋅⋅H⋅⋅⋅N system is accompanied by substantially different molecular conformations and, subsequently, by divergent supramolecular architectures. The appearance and interconversion conditions for each of the four phases have been established on the basis of a number of solution and solvent-free experiments, and evaluated against the results of computational studies. Solid phases readily convert into the most stable form (D1 a) upon exposure to methanol vapor, heating, or by mechanical treatment, and these transformations are accompanied by a change in the color of the sample. The course of thermally induced transformations has been monitored in detail by means of temperature-resolved powder X-ray diffraction and infrared spectroscopy. Upon dissolution, all forms equilibrate immediately, as confirmed by NMR and UV/Vis spectroscopy in several solvents, with the equilibrium shifted far towards the enol tautomer. This study reveals the significance of peripheral groups in the stabilization of metastable tautomers in the solid state.

Supramolecular stabilization of metastable tautomers in solution and the solid state.

This work presents a successful application of a recently reported supramolecular strategy for stabilization of metastable tautomers in cocrystals to monocomponent, non-heterocyclic, tautomeric solids. Quantum-chemical computations and solution studies show that the investigated Schiff base molecule, derived from 3-methoxysalicylaldehyde and 2-amino-3-hydroxypyridine (ap), is far more stable as the enol tautomer. In the solid state, however, in all three obtained polymorphic forms it exists solely as the keto tautomer, in each case stabilized by an unexpected hydrogen-bonding pattern. Computations have shown that hydrogen bonding of the investigated Schiff base with suitable molecules shifts the tautomeric equilibrium to the less stable keto form. The extremes to which supramolecular stabilization can lead are demonstrated by the two polymorphs of molecular complexes of the Schiff base with ap. The molecules of both constituents of molecular complexes are present as metastable tautomers (keto anion and protonated pyridine, respectively), which stabilize each other through a very strong hydrogen bond. All the obtained solid forms proved stable in various solid-state and solvent-mediated methods used to establish their relative thermodynamic stabilities and possible interconversion conditions.

Thermodynamic study of dihydrogen phosphate dimerisation and complexation with novel urea- and thiourea-based receptors.

Complexation of dihydrogen phosphate by novel thiourea and urea receptors in acetonitrile and dimethyl sulfoxide was studied in detail by an integrated approach by using several methods (isothermal titration calorimetry, ESI-MS, and (1)H NMR and UV spectroscopy). Thermodynamic investigations into H2PO4(-) dimerisation, which is a process that has been frequently recognised, but rarely quantitatively described, were carried out as well. The corresponding equilibrium was taken into account in the anion-binding studies, which enabled reliable determination of the complexation thermodynamic quantities. In both solvents the thiourea derivatives exhibited considerably higher binding affinities with respect to those containing the urea moiety. In acetonitrile, 1:1 and 2:1 (anion/receptor) complexes formed, whereas in dimethyl sulfoxide only the significantly less stable complexes of 1:1 stoichiometry were detected. The solvent effects on the thermodynamic parameters of dihydrogen phosphate dimerisation and complexation reactions are discussed.

Complexation of fluoride anion and its ion pairs with alkali metal cations by tetra-substituted lower rim calix[4]arene tryptophan derivative

Abstract Selective binding of fluoride anion and its alkali metal cation ion pairs by a fluorescent calix[4]arene (L) derivative bearing tryptophan moieties was studied in acetonitrile at 25 °C. It was found that LF− and LF22− complexes were formed and their stability constants were determined by means of UV and 1H NMR titrations. Both amide and indole NH groups were involved in the stabilisation of the fluoride complexes, i.e. L afforded two anion-binding sites. 1H NMR titrations provided evidence of simultaneous complexation of both Na+ cation and fluoride anion resulting in the formation of a ternary NaLF complex. In this ion pair complex, the Na+ cation was most probably bound primarily by the calixarene ether and amide oxygen atoms, whereas the indole NH groups interacted with the fluoride ion. A highly favourable ion pairing between Na+ and F– in acetonitrile was studied using potentiometric measurements. The results pointed out the importance of fluoride pairing with alkali metal cations in aprotic organic solvents and the necessity of taking these reactions into account in the course of speciation studies of such solutions.

Amino acid-based tweezers: the role of turn-like conformation in the binding of copper(II).

The importance of turn-like peptide conformation for the copper(II) binding has been revealed by the synthesis of simple amino acid-based tweezers and the study of their interaction with copper(II). Amino acids Phe, Leu, Val, Ala and Gly were bridged through their C-terminuses with conformationally constrained motif, cis enediyne moiety ((Z)-octa-4-en-2,6-diyne-1,8-diamine). The interaction of prepared diamine ligands with copper(II) was studied by means of potentiometric titrations, UV-visible and EPR spectroscopic and mass spectrometric techniques. All ligands interact efficiently with copper(II) and form complexes of 1:1 stoichiometry differing in the protonation state of the ligand. LCu(2+) species were found predominant at pH<6.5, with log K* ranging from -8.06 to -6.65, while at higher pH deprotonation occurred, giving rise to LH(-1)Cu(+) complexes or LH(-2)Cu complex for the phenylalanine-related ligand. An additional species, LH(-3)Cu(-) were found at pH>9 for the valine- and alanine-related ligands, respectively. Comparing stability of studied complexes with those reported in previous work revealed that ligands effectively emulate properties of copper(II) binding peptides. Based on the results obtained in this work it can be concluded that structural rigidity significantly enhances coordination properties of the ligand, thus conforming importance of the turn-like peptide conformation for the copper(II) binding.

Acid-base properties of phosphoric and acetic acid in aprotic organic solvents – A complete thermodynamic characterisation

Knowledge regarding the acid-base behaviour in non-aqueous media has remained relatively scarce in spite of its importance for many aspects of chemistry. The research presented in this work fills some of particularly important gaps in the corresponding thermodynamic data. We report on a detailed study of acid-base properties of dihydrogen phosphate and acetate in aprotic organic solvents (acetonitrile, dimethyl sulfoxide, and dimethylformamide). It was found that several processes, i.e. protonation, homoassociation, and dimerisation play important roles in defining the basicity of these widely important anions. In the case of dihydrogen phosphate, formation of higher homoassociates (two anions, one acid molecule and vice versa) was detected, whereas acetate formed only simple homoassociates of 1:1 stoichiometry. The dimerisation of dihydrogen phosphate and acetic acid were confirmed to be important processes as well. The thermodynamics of the above mentioned reactions was characterised in detail by means of various experimental methods: ITC, spectrophotometry, NMR-spectroscopy, and conductometry. Reliable equilibrium constants and other thermodynamic reaction functions were determined. The obtained results were discussed in terms of hydrogen bonding potential of the anions and their conjugated acids, as well as solvent properties, i.e. their ability to solvate the species involved in the studied processes.

Dehydroacetic acid derivatives bearing amide and urea moieties as effective anion receptors

Derivatives of dehydroacetic acid comprising amide or urea subunits have been synthesized and their anion-binding properties investigated. Among a series of halides and oxyanions, the studied compounds selectively bind acetate and dihydrogen phosphate in acetonitrile and dimethyl sulfoxide. The corresponding complexation processes were characterized by means of 1 H NMR titrations, which revealed a 1:1 complex stoichiometry in most cases, with the exception of dihydrogen phosphate, which formed 2:1 (anion/ligand) complexes in acetonitrile. The complex stability constants were determined and are discussed with respect to the structural properties of the receptors, the hydrogen-bond-forming potential of the anions, and the characteristics of the solvents used. Based on the spectroscopic data and results of Monte Carlo simulations, the amide or urea groups were affirmed as the primary binding sites in all cases. The results of the computational methods indicate that an array of both inter- and intramolecular hydrogen bonds can form in the studied systems, and these were shown to play an important role in defining the overall stability of the complexes. Solubility measurements were carried out in both solvents and the thermodynamics of transfer from acetonitrile to dimethyl sulfoxide were characterized on a quantitative level. This has afforded a detailed insight into the impact of the medium on the complexation reactions.